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1.
Clin. transl. oncol. (Print) ; 25(10): 2950-2959, oct. 2023. tab, graf
Artigo em Inglês | IBECS | ID: ibc-225076

RESUMO

Introduction/objectives To describe abemaciclib use in patients with hormone receptor-positive, human epidermal growth factor receptor-negative (HR+/HER2−) metastatic breast cancer (mBC) who participated in the Named Patient Use program (NPU) in Spain.Material and methods This retrospective study was based on medical record review of patients across 20 centers during 2018/2019. Patients were followed up until death, enrolment in a clinical trial, loss of follow-up or study end. Clinical and demographic characteristics, treatment patterns and abemaciclib effectiveness were analyzed; time-to-event and median times were estimated using the Kaplan–Meier (KM) method. Results The study included 69 female patients with mBC (mean age 60.4 ± 12.4 years), 86% of whom had an initial diagnosis of early BC and 20% had an ECOG ≥ 2. Median follow-up was 23 months (range 16–28). Metastases were frequently observed in bone (79%) and visceral tissue (65%), with 47% having metastases in > 2 sites. Median number of treatment lines before abemaciclib was 6 (range 1–10). Abemaciclib monotherapy was received by 72% of patients and combination therapy with endocrine therapy by 28% of patients; 54% of patients required dose adjustments, with a median time to first adjustment of 1.8 months. Abemaciclib was discontinued in 86% of patients after a median of 7.7 months (13.2 months for combination therapy and 7.0 months for monotherapy) mainly due to disease progression (69%). Conclusion These results suggest that abemaciclib is effective, as monotherapy and in combination, for patients with heavily pretreated mBC, consistent with clinical trial results (AU)


Assuntos
Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Neoplasias da Mama/metabolismo , Neoplasias da Mama/tratamento farmacológico , Antineoplásicos/administração & dosagem , Receptor ErbB-2/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estudos Retrospectivos , Espanha
2.
Clin. transl. oncol. (Print) ; 25(10): 3042-3056, oct. 2023. ilus, tab, graf
Artigo em Inglês | IBECS | ID: ibc-225084

RESUMO

Background Belonging to the G-protein coupled receptor 1 family, G protein-coupled receptor 176 (GPR176) is associated with the Gz/Gx G-protein subclass and is capable of decreasing cAMP production. Methods GPR176 expression was detected by qRT-PCR, bioinformatics analysis, Western blot and immunohistochemistry, and compared with clinicopathological characteristics of breast cancer. GPR176-related genes and pathways were subjected to bioinformatic analysis. We also explored the effects of GPR176 on the phenotypes of breast cancer cells. Results Lower expression of GPR176 mRNA was seen in breast cancer than in normal tissues, but the opposite pattern was found for its protein (p < 0.05). GPR176 mRNA was associated with female sex, low T staging, non-Her-2+ subtypes, non-mutant p53 status in breast cancer (p < 0.05). GPR176 methylation was negatively correlated with its mRNA level and T staging in breast cancer, and was higher in breast cancer than normal tissues (p < 0.05). GPR176 protein expression was positively correlated with older age, small tumor size, and non-luminal-B subtype of breast cancers (p < 0.05). The differential genes of GPR176 were involved in receptor-ligand interaction, RNA maturation, and so forth (p < 0.05). GPR176-related genes were categorized into cell mobility, membrane structure, and so on (p < 0.05). GPR176 knockdown weakened the proliferation, glucose catabolism, anti-apoptosis, anti-pyroptosis, migration, invasion, and epithelial-mesenchymal transition of breast cancer cells. Conclusion These results indicate that GPR176 might be involved in the tumorigenesis and subsequent progression of breast cancer by deteriorating aggressive phenotypes. It might be utilized as a potential biomarker to indicate the aggressive behaviors and poor prognosis of breast cancer and a potential target of genetic therapy (AU)


Assuntos
Humanos , Feminino , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Terapia Genética , Regulação Neoplásica da Expressão Gênica , RNA Mensageiro/genética , Biomarcadores Tumorais , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Prognóstico , Fenótipo
3.
Rev. esp. med. nucl. imagen mol. (Ed. impr.) ; 42(5): 318-323, sept.- oct. 2023. ilus, tab, graf
Artigo em Espanhol | IBECS | ID: ibc-225090

RESUMO

Objetivo Este estudio evalúa el papel pronóstico de diferentes criterios de respuesta metabólica de la PET/TC con [18F]FDG en pacientes con cáncer de mama metastásico (CMM) tratadas con inhibidores de la cinasa dependiente de ciclina 4/6 (CDK 4/6). Materiales y métodos Evaluamos retrospectivamente los datos de pacientes con CMM tratados con inhibidores de CDK 4/6 a los que se les realizó una [18F]FDG PET/TC antes de iniciar y durante el tratamiento. La respuesta de [18F]FDG PET/CT se evaluó con la Organización Europea para la Investigación y el Tratamiento del Cáncer, los criterios de respuesta de PET en tumores sólidos (PERCIST) y los criterios de glucólisis de lesión total de cuerpo entero (WBTLG). Fleiss kappa se calculó para evaluar la concordancia entre los criterios de respuesta metabólica. El criterio de valoración del estudio fue la supervivencia libre de progresión (PFS). Los datos de SLP se analizaron mediante el método de Kaplan-Meier y se compararon mediante la prueba de rango logarítmico. Resultados El estudio incluyó a 16 pacientes con CMM que recibieron terapia con inhibidores de CDK 4/6. Según PERCIST, se encontró respuesta metabólica parcial (PMR) en siete pacientes, enfermedad metabólica estable (SMD) en siete pacientes y enfermedad metabólica progresiva (PMD) en dos pacientes. Según la Organización Europea para la Investigación y el Tratamiento del Cáncer, se detectó PMR en ocho pacientes, SMD en siete pacientes y PMD en un paciente. Según WBTLG, se encontró PMR en 10 pacientes, SMD en cuatro pacientes y PMD en dos pacientes. Hubo un acuerdo justo entre los tres criterios. Si bien se detectó progresión en siete de los pacientes durante el seguimiento, no se detectó progresión en nueve de ellos. El análisis de Kaplan-Meier reveló que los que respondieron según WBTLG mostraron una SLP significativamente más larga que los que no respondieron (AU)


Purpose This study evaluates the prognostic role of different [18F]FDG PET/CT metabolic response criteria in metastatic breast cancer (MBC) patients treated with cyclin-dependent kinase 4/6 inhibitors (CDK 4/6). Materials and methods We retrospectively evaluated the data of MBC patients treated with CDK 4/6 inhibitors who underwent an [18F]FDG PET/CT scan before starting and during treatment. [18F]FDG PET/CT response was assessed with the European Organization for Research and Treatment of Cancer, PET response criteria in solid tumors (PERCIST), and whole-body total lesion glycolysis (WBTLG) criteria. Fleiss kappa was computed to assess the agreement between metabolic response criteria. The endpoint of the study was progression-free survival (PFS). PFS data were analyzed by the Kaplan–Meier method and compared using the log-rank test. Results The study included 16 MBC patients who received CDK 4/6 inhibitors therapy. According to PERCIST, partial metabolic response (PMR) was found in seven patients, stable metabolic disease (SMD) in seven patients, and progressive metabolic disease (PMD) in two patients. According to the European Organization for Research and Treatment of Cancer, PMR was detected in eight patients, SMD in seven patients, and PMD in one patient. According to WBTLG, PMR was found in 10 patients, SMD in four patients, and PMD in two patients. There was a fair agreement between the three criteria. While progression was detected in seven of the patients during follow-up, no progression was detected in nine of them. Kaplan–Meier analysis revealed that the responders according to WBTLG showed significantly longer PFS than non-responders. Conclusion Treatment response according to WBTLG criteria during treatment appears to be associated with prolonged PFS in patients treated with CDK 4/6 inhibitors for MBC (AU)


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Metástase Neoplásica , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Estudos Retrospectivos , Prognóstico
4.
Future Med Chem ; 15(13): 1133-1147, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37529897

RESUMO

Background: Targeting CDK4/6 has advanced breast cancer treatment. Herein, new quinazolinones were synthesized with acetamide linkers as potential anti-breast cancer agents. Methods & results: In vitro cytotoxic evaluation on human breast cancer cell lines (MCF7 and MDA-MB-231) identified 1,3-benzodioxole (5d) to be of the highest potency. It showed good inhibitory activity on CDK4/6. Compound 5d arrested the cell cycle at the G1-phase, caused induction of early and late apoptosis in an Annexin V-FITC assay, led to an increase in the level of caspase-3 and upregulated Bax expression and downregulated Bcl-2 in MCF7 cells. Compound 5d showed good radiosensitizing activity when combined with a single dose of 8-Gy γ-radiation. Conclusion: This study introduces quinazolinone scaffolds as new CDK4/6 inhibitors for breast cancer.


Assuntos
Antineoplásicos , Neoplasias da Mama , Humanos , Feminino , Proliferação de Células , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Quinazolinonas/farmacologia , Ciclo Celular , Apoptose , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Quinase 4 Dependente de Ciclina/metabolismo
5.
Nanotechnology ; 34(46)2023 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-37527629

RESUMO

Folate receptor-targeted therapy has excellent prospects for the treatment of breast cancer. A non-toxic concentration of folate-conjugated palladium-based nanoparticles was used to target the overexpressed folate receptor on breast cancer cells. The folate-conjugated nanoparticles were tailored to accumulate selectively in cancer cells relative to normal cells via the folate receptor. The MDA-MB-231, MDA-MB-468, MCF-7 breast cancer cell lines, and MCF-10A normal cell lines were used in the study. Qualitative and quantitative analysis of nanoparticle cellular uptake and accumulation was conducted using transmission electron microscopy and inductively coupled plasma-optical emission spectroscopy. The findings proved that folate-conjugated palladium nanoparticles successfully and preferentially accumulated in breast cancer cells. We conclude that folate-conjugated palladium nanoparticles can be potentially used to target breast cancer cells for radiopharmaceutical applications.


Assuntos
Neoplasias da Mama , Nanopartículas Metálicas , Nanopartículas , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Paládio/farmacologia , Nanopartículas Metálicas/química , Ácido Fólico/química , Nanopartículas/química , Células MCF-7 , Linhagem Celular Tumoral
6.
Acta Biomater ; 169: 192-208, 2023 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-37541606

RESUMO

Although mitochondrial morphology and function are considered to be closely related to matrix stiffness-driven tumor progression, it remains poorly understood how extracellular matrix (ECM) stiffness affects mitochondrial dynamics and mitophagy. Here, we found that soft substrate triggered calcium transport by increasing endoplasmic reticulum (ER) calcium release and mitochondrial (MITO) calcium uptake. ER-MITO calcium transport promoted the recruitment of dynamin-related protein 1 (Drp1) to mitochondria and phosphorylation at the serine 616 site, which induced mitochondrial fragmentation and Parkin/PINK1-mediated mitophagy. Furthermore, in vivo experiments demonstrated that soft ECM enhanced calcium levels in tumor tissue, Drp1 activity was required for soft ECM-induced mitochondrial dynamics impairment, and inhibition of Drp1 activity enhanced soft ECM-induced tumor necrosis. In conclusion, we revealed a new mechanism whereby ER-MITO calcium transport regulated mitochondrial dynamics and mitophagy through Drp1 translocation in response to soft substrates. These findings provide valuable insights into ECM stiffness as a potential target for antitumor therapy. STATEMENT OF SIGNIFICANCE: Here, we examined the relationship between substrate stiffness and mitochondrial dynamics by using polyacrylamide (PAA) substrates to simulate the stages of breast cancer or BAPN to reduce tumor tissue stiffness. The results elucidated that soft substrate triggered the recruitment of DRP1 and subsequent mitochondrial fission and mitophagy by ER-MITO calcium transport. Furthermore, mitophagy partly attenuated soft ECM-mediated tumor tissue necrosis and contributed to tumor survival in vivo. Our discoveries revealed the molecular mechanisms by which mechanical stimulation regulates mitochondrial dynamics, providing valuable insights into ECM stiffness as a target for anti-tumor approaches, which could be beneficial for both biomechanics research and clinical applications.


Assuntos
Neoplasias da Mama , Mitofagia , Humanos , Feminino , Mitofagia/fisiologia , Dinâmica Mitocondrial , Cálcio/metabolismo , Dinaminas/metabolismo , Retículo Endoplasmático/metabolismo , Necrose/metabolismo , Neoplasias da Mama/metabolismo
7.
J Med Chem ; 66(16): 11351-11364, 2023 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-37578941

RESUMO

Interplay between breast cancer (BC) cells and the tumor microenvironment (TME) influences the outcome of cancer treatment. Aberrant activation of signal transducer and activator of transcription 3 (STAT3) promotes the interaction and causes immunosuppression and drug resistance. Platinum(IV) complexes SPP and DPP bearing pterostilbene-derived axial ligand(s) were synthesized to inhibit the JAK2-STAT3 pathway in BC cells and regulate the TME. These complexes exerted remarkable antiproliferative activity against the triple-negative BC cells, suppressed the expression of phosphorylated STAT3 and STAT3-related cyclooxygenase-2 and IL-6, and activated caspase-3 and cleaved poly ADP-ribose polymerase, preventing the repair of DNA lesions and inducing apoptosis. Furthermore, DPP promoted the maturation and antigen presentation of dendritic cells, repressed the proliferation and differentiation of myeloid-derived suppressor cells and regulatory T cells, and facilitated the expansion of T cells. As a consequence, DPP showed excellent anticancer activity against BC with almost no general toxicity in vivo as a potential chemoimmunotherapeutic agent.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Platina/farmacologia , Platina/metabolismo , Linhagem Celular Tumoral , Fator de Transcrição STAT3/metabolismo , Microambiente Tumoral , Apoptose , Proliferação de Células
8.
Med Oncol ; 40(9): 263, 2023 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-37548777

RESUMO

Although triple-negative breast cancer accounts for less than one-fifth of breast cancers, it has a higher rate of metastasis and mortality. This study investigated the effects of combination treatment with paclitaxel and celecoxib on the expression of genes involved in the apoptosis of triple-negative metastatic breast cancer cells. MDA-MB-231 cells were cultured and then treated with certain concentrations of celecoxib (CLX), paclitaxel (PTX), and combination of them for 24 and 48 h. Cell viability was assessed by the MTT method. The real-time PCR method was utilized to assess the expression level of the genes involved in apoptosis. Western blotting was used for evaluating protein expression. IC50 values for CLX and PTX were 73.95 µM and 3.15 µM, respectively. The results demonstrated that PTX, CLX, and PTX + CLX significantly (p < 0.05) reduced cell viability. The comparison of combination treatment with PTX showed a significant increase in caspase 3 gene expression at both time points, in Bax gene expression after 48 h, and a remarkable decrease in Bcl-2 gene expression at both times. Western blotting results were in line with genes' expression. These findings indicate that a combination of PTX and CLX results in a significantly more reduction in cell viability of breast cancer cells. In addition, it seems CLX may be an effective agent in regulating the expression level of caspase 3, Bax, and Bcl-2 when combined with PTX.


Assuntos
Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Paclitaxel/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Celecoxib/farmacologia , Caspase 3/metabolismo , Proteína X Associada a bcl-2/metabolismo , Linhagem Celular Tumoral , Apoptose , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo
9.
Med Oncol ; 40(9): 267, 2023 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-37567972

RESUMO

Estrogen receptor-positive (ER+) breast cancer represents approximately two-thirds of all breast cancers and has a sustained risk of late disease recurrence. Combining cyclin-dependent kinase 4/6 (CDK4/6) inhibitors with anti-estrogen therapies significantly improves ER+ advanced breast cancer clinical outcomes. Despite promising clinical outcomes, intrinsic or acquired resistance to CDK4/6 inhibitors has limited their success. We used CRISPR to screen MCF-7 cells to explore the targets whose inhibition is synthetic lethal with CDK4/6 inhibitors in ER+ breast cancer cells. We found that GATA zinc finger domain containing 1 (GATAD1) is a new synthetic lethal target with CDK4/6 inhibitors in ER+ breast cancer cells. Mechanistically, GATAD1 promotes cell proliferation by transcriptionally inhibiting p21 in ER+ breast cancer cells. GATAD1 depletion decreased the phosphorylation of CDK2/4 and RB transcriptional corepressor 1 (RB1), inducing cell cycle arrest. P21 overexpression abolished the enhanced proliferation induced by GATAD1 overexpression. Our results identify GATAD1 as a therapeutic target in ER+ breast cancer, which is beneficial to provide a novel treatment strategy.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Receptores de Estrogênio/metabolismo , Quinase 4 Dependente de Ciclina/metabolismo , Linhagem Celular Tumoral , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Quinase 6 Dependente de Ciclina , Recidiva Local de Neoplasia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Proteínas do Olho/uso terapêutico
10.
Breast Cancer Res ; 25(1): 99, 2023 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-37608351

RESUMO

BACKGROUND: Obesity increases breast cancer risk and breast cancer-specific mortality, particularly for people with estrogen receptor (ER)-positive tumors. Body mass index (BMI) is used to define obesity, but it may not be the best predictor of breast cancer risk or prognosis on an individual level. Adult weight gain is an independent indicator of breast cancer risk. Our previous work described a murine model of obesity, ER-positive breast cancer, and weight gain and identified fibroblast growth factor receptor (FGFR) as a potential driver of tumor progression. During adipose tissue expansion, the FGF1 ligand is produced by hypertrophic adipocytes as a stimulus to stromal preadipocytes that proliferate and differentiate to provide additional lipid storage capacity. In breast adipose tissue, FGF1 production may stimulate cancer cell proliferation and tumor progression. METHODS: We explored the effects of FGF1 on ER-positive endocrine-sensitive and resistant breast cancer and compared that to the effects of the canonical ER ligand, estradiol. We used untargeted proteomics, specific immunoblot assays, gene expression profiling, and functional metabolic assessments of breast cancer cells. The results were validated in tumors from obese mice and breast cancer datasets from women with obesity. RESULTS: FGF1 stimulated ER phosphorylation independently of estradiol in cells that grow in obese female mice after estrogen deprivation treatment. Phospho- and total proteomic, genomic, and functional analyses of endocrine-sensitive and resistant breast cancer cells show that FGF1 promoted a cellular phenotype characterized by glycolytic metabolism. In endocrine-sensitive but not endocrine-resistant breast cancer cells, mitochondrial metabolism was also regulated by FGF1. Comparison of gene expression profiles indicated that tumors from women with obesity shared hallmarks with endocrine-resistant breast cancer cells. CONCLUSIONS: Collectively, our data suggest that one mechanism by which obesity and weight gain promote breast cancer progression is through estrogen-independent ER activation and cancer cell metabolic reprogramming, partly driven by FGF/FGFR. The first-line treatment for many patients with ER-positive breast cancer is inhibition of estrogen synthesis using aromatase inhibitors. In women with obesity who are experiencing weight gain, locally produced FGF1 may activate ER to promote cancer cell metabolic reprogramming and tumor progression independently of estrogen.


Assuntos
Neoplasias da Mama , Fator 1 de Crescimento de Fibroblastos , Receptores de Estrogênio , Animais , Feminino , Camundongos , Estradiol , Estrogênios , Fator 1 de Crescimento de Fibroblastos/metabolismo , Ligantes , Obesidade/complicações , Proteômica , Receptores de Estrogênio/genética , Aumento de Peso , Neoplasias da Mama/metabolismo
11.
Int J Mol Sci ; 24(15)2023 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-37569363

RESUMO

In this study, we investigated the potential anticancer effects of Viscum album, a parasitic plant that grows on Malus domestica (VaM) on breast cancer cells, and explored the underlying mechanisms. VaM significantly inhibited cell viability and proliferation and induced apoptosis in a dose-dependent manner. VaM also regulated cell cycle progression and effectively inhibited activation of the STAT3 signaling pathway through SHP-1. Combining VaM with low-dose doxorubicin produced a synergistic effect, highlighting its potential as a promising therapeutic. In vivo, VaM administration inhibited tumor growth and modulated key molecular markers associated with breast cancer progression. Overall, our findings provide strong evidence for the therapeutic potential of VaM in breast cancer treatment and support further studies exploring clinical applications.


Assuntos
Neoplasias da Mama , Viscum album , Humanos , Feminino , Viscum album/metabolismo , Neoplasias da Mama/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Apoptose , Transdução de Sinais , Proliferação de Células , Linhagem Celular Tumoral , Fator de Transcrição STAT3/metabolismo
12.
Int J Mol Sci ; 24(15)2023 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-37569585

RESUMO

In healthy tissues, cells are in mechanical homeostasis. During cancer progression, this equilibrium is disrupted. Cancer cells alter their mechanical phenotype to a softer and more fluid-like one than that of healthy cells. This is connected to cytoskeletal remodeling, changed adhesion properties, faster cell proliferation and increased cell motility. In this work, we investigated the mechanical properties of breast cancer cells representative of different breast cancer subtypes, using MCF-7, tamoxifen-resistant MCF-7, MCF10A and MDA-MB-231 cells. We derived viscoelastic properties from atomic force microscopy force spectroscopy measurements and showed that the mechanical properties of the cells are associated with cancer cell malignancy. MCF10A are the stiffest and least fluid-like cells, while tamoxifen-resistant MCF-7 cells are the softest ones. MCF-7 and MDA-MB-231 show an intermediate mechanical phenotype. Confocal fluorescence microscopy on cytoskeletal elements shows differences in actin network organization, as well as changes in focal adhesion localization. These findings provide further evidence of distinct changes in the mechanical properties of cancer cells compared to healthy cells and add to the present understanding of the complex alterations involved in tumorigenesis.


Assuntos
Neoplasias da Mama , Citoesqueleto , Humanos , Feminino , Linhagem Celular Tumoral , Citoesqueleto/metabolismo , Células MCF-7 , Actinas/metabolismo , Tamoxifeno/farmacologia , Tamoxifeno/metabolismo , Neoplasias da Mama/metabolismo , Microscopia de Força Atômica/métodos
13.
Int J Mol Sci ; 24(15)2023 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-37569777

RESUMO

Human colostrum and milk contain diverse cells and soluble components that have the potential to act against tumors. In breast cancer, macrophages play a significant role in immune infiltration and contribute to the progression and spread of tumors. However, studies suggest that these cells can be reprogrammed to act as an antitumor immune response. This study aimed to evaluate the levels of melatonin and its receptors, MT1 (melatonin receptor 1) and MT2 (melatonin receptor 2), in colostrum and assess the differentiation and polarization of the colostrum macrophages modulated by melatonin in the presence of breast tumor cells. Colostrum samples were collected from 116 mothers and tested for their melatonin and receptor levels. The colostrum cells were treated with or without melatonin and then cultured for 24 h in the presence or absence of breast tumor cells. The results showed that melatonin treatment increased the expression of MT1 and MT2 in the colostrum cells. Furthermore, melatonin treatment increased the percentage of M1 macrophages and decreased the percentage of M2 macrophages. When the colostrum macrophages were cocultured with breast tumor cells, melatonin reduced the percentage of both macrophage phenotypes and the cytokines tumor necrosis factor-alpha (TNF-α) and interleukin 8 (IL-8). These data suggest that melatonin can regulate the inflammatory process via M1 macrophages in the tumor microenvironment and, simultaneously, the progression of M2 macrophages that favor tumorigenesis.


Assuntos
Neoplasias da Mama , Melatonina , Feminino , Gravidez , Humanos , Colostro/metabolismo , Melatonina/farmacologia , Melatonina/metabolismo , Receptores de Melatonina/metabolismo , Macrófagos/metabolismo , Linhagem Celular Tumoral , Neoplasias da Mama/metabolismo , Microambiente Tumoral
14.
Int J Mol Sci ; 24(15)2023 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-37569854

RESUMO

Numerous in vitro and in vivo studies have shown that curcumin primarily activates apoptotic pathways in cancer cells and inhibits cancer progression by modulating various molecular targets. In this study, we utilized reverse docking servers to predict 444 human proteins that may potentially be targeted by curcumin. Then, high-throughput assays were conducted by using RNA-seq technology on curcumin-treated MCF-7 (human breast cancer ER (+)) and MDA-MB-231 (human breast cancer ER(-)/TNBC) cancer cell lines. Enrichment analysis identified seven and eight significantly down-regulated signaling pathways in these two cell lines, where the enriched genes were used to construct protein-protein interaction networks. From these networks, the MCODE algorithm screened out 42 hub targets, which are core genes of the RTK-(PI3K-AKT)/(MEK/ERK1/2) crosstalk network. Genetic alteration and expression patterns of hub targets of curcumin may be closely related to the overall pathogenesis and prognosis of breast cancer. MAPKAPK3, AKT3, CDK5, IGF1R, and MAPK11 are potential prognostic markers and therapeutic targets of curcumin in patients with triple-negative breast cancer. Molecular docking and transcriptomic results confirmed that curcumin can inhibit these high-scoring targets at the protein level. Additionally, these targets can act as self-feedback factors, relying on the cascading repressive effects in the network to limit their own transcription at the mRNA level. In conclusion, the integration of transcriptomic and molecular docking approaches enables the rapid identification of dual or multiple inhibitory targets of curcumin in breast cancer. Our study provides the potential elucidation of the anti-cancer mechanism of curcumin.


Assuntos
Neoplasias da Mama , Curcumina , Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Curcumina/farmacologia , Curcumina/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Transcriptoma , Simulação de Acoplamento Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Neoplasias de Mama Triplo Negativas/patologia
15.
Molecules ; 28(15)2023 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-37570868

RESUMO

Breast cancer patients are characterized by the oncobiotic transformation of multiple microbiome communities, including the gut microbiome. Oncobiotic transformation of the gut microbiome impairs the production of antineoplastic bacterial metabolites. The goal of this study was to identify bacterial metabolites with antineoplastic properties. We constructed a 30-member bacterial metabolite library and screened the library compounds for effects on cell proliferation and epithelial-mesenchymal transition. The metabolites were applied to 4T1 murine breast cancer cells in concentrations corresponding to the reference serum concentrations. However, yric acid, glycolic acid, d-mannitol, 2,3-butanediol, and trans-ferulic acid exerted cytostatic effects, and 3-hydroxyphenylacetic acid, 4-hydroxybenzoic acid, and vanillic acid exerted hyperproliferative effects. Furthermore, 3-hydroxyphenylacetic acid, 4-hydroxybenzoic acid, 2,3-butanediol, and hydrocinnamic acid inhibited epithelial-to-mesenchymal (EMT) transition. We identified redox sets among the metabolites (d-mannitol-d-mannose, 1-butanol-butyric acid, ethylene glycol-glycolic acid-oxalic acid), wherein only one partner within the set (d-mannitol, butyric acid, glycolic acid) possessed bioactivity in our system, suggesting that changes to the local redox potential may affect the bacterial secretome. Of the nine bioactive metabolites, 2,3-butanediol was the only compound with both cytostatic and anti-EMT properties.


Assuntos
Antineoplásicos , Neoplasias da Mama , Citostáticos , Humanos , Animais , Camundongos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Transição Epitelial-Mesenquimal , Citostáticos/farmacologia , Ácido Butírico/farmacologia , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Proliferação de Células
16.
N Engl J Med ; 389(7): 612-619, 2023 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-37585627

RESUMO

BACKGROUND: Adjuvant radiotherapy is prescribed after breast-conserving surgery to reduce the risk of local recurrence. However, radiotherapy is inconvenient, costly, and associated with both short-term and long-term side effects. Clinicopathologic factors alone are of limited use in the identification of women at low risk for local recurrence in whom radiotherapy can be omitted. Molecularly defined intrinsic subtypes of breast cancer can provide additional prognostic information. METHODS: We performed a prospective cohort study involving women who were at least 55 years of age, had undergone breast-conserving surgery for T1N0 (tumor size <2 cm and node negative), grade 1 or 2, luminal A-subtype breast cancer (defined as estrogen receptor positivity of ≥1%, progesterone receptor positivity of >20%, negative human epidermal growth factor receptor 2, and Ki67 index of ≤13.25%), and had received adjuvant endocrine therapy. Patients who met the clinical eligibility criteria were registered, and Ki67 immunohistochemical analysis was performed centrally. Patients with a Ki67 index of 13.25% or less were enrolled and did not receive radiotherapy. The primary outcome was local recurrence in the ipsilateral breast. In consultation with radiation oncologists and patients with breast cancer, we determined that if the upper boundary of the two-sided 90% confidence interval for the cumulative incidence at 5 years was less than 5%, this would represent an acceptable risk of local recurrence at 5 years. RESULTS: Of 740 registered patients, 500 eligible patients were enrolled. At 5 years after enrollment, recurrence was reported in 2.3% of the patients (90% confidence interval [CI], 1.3 to 3.8; 95% CI, 1.2 to 4.1), a result that met the prespecified boundary. Breast cancer occurred in the contralateral breast in 1.9% of the patients (90% CI, 1.1 to 3.2), and recurrence of any type was observed in 2.7% (90% CI, 1.6 to 4.1). CONCLUSIONS: Among women who were at least 55 years of age and had T1N0, grade 1 or 2, luminal A breast cancer that were treated with breast-conserving surgery and endocrine therapy alone, the incidence of local recurrence at 5 years was low with the omission of radiotherapy. (Funded by the Canadian Cancer Society and the Canadian Breast Cancer Foundation; LUMINA ClinicalTrials.gov number, NCT01791829.).


Assuntos
Neoplasias da Mama , Mastectomia Segmentar , Recidiva Local de Neoplasia , Radioterapia Adjuvante , Feminino , Humanos , Neoplasias da Mama/classificação , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Canadá , Antígeno Ki-67/biossíntese , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/prevenção & controle , Estudos Prospectivos , Prognóstico , Pessoa de Meia-Idade , Receptores de Estrogênio/biossíntese , Receptores de Progesterona/biossíntese , Receptor ErbB-2/biossíntese , Antineoplásicos Hormonais/uso terapêutico
17.
Kaohsiung J Med Sci ; 39(9): 873-882, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37584416

RESUMO

This study was to explore the regulatory effect of long non-coding RNA LINC01559 on Docetaxel resistance in breast carcinoma (BCa) and its underlying mechanism. In the present study, we found that LINC01559 expression was elevated and LINC01559 overexpression facilitated docetaxel resistance in BCa cells. Moreover, it was revealed that the upregulation of LINC01559 in BCa cells was induced by FTO-mediated demethylation in an m6A-YTHDF2-dependent manner. Additionally, Dual-luciferase reporter assay confirmed the binding ability between LINC01559 and miR-1343-3p, and Pearson correlation analysis showed a negative correlation between them. Particularly, miR-1343-3p inhibition partly abolished the suppression on docetaxel resistance in BCa cells caused by LINC01559 knockdown. To sum up, FTO-mediated epigenetic upregulation of LINC01559 promoted cell resistance to Docetaxel in BCa by negatively regulating miR-1343-3p.


Assuntos
Neoplasias da Mama , MicroRNAs , Humanos , Feminino , Docetaxel/farmacologia , Regulação para Cima/genética , MicroRNAs/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Epigênese Genética , Proliferação de Células , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Dioxigenase FTO Dependente de alfa-Cetoglutarato/metabolismo
18.
Mol Pharm ; 20(9): 4629-4639, 2023 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-37552575

RESUMO

One of the most aggressive forms of breast cancer involves the overexpression of human epidermal growth factor receptor 2 (HER2). HER2 is overexpressed in ∼25% of all breast cancers and is associated with increased proliferation, increased rates of metastasis, and poor prognosis. Treatment for HER2-positive breast cancer has vastly improved since the development of the monoclonal antibody trastuzumab (Herceptin) as well as other biological constructs. However, patients still commonly develop resistance, illustrating the need for newer therapies. Nanobodies have become an important focus for potential development as HER2-targeting imaging agents and therapeutics. Nanobodies have many favorable characteristics, including high stability in heat and nonphysiological pH, while maintaining their low-nanomolar affinity for their designed targets. Specifically, the 2Rs15d nanobody has been developed for targeting HER2 and has been evaluated as a diagnostic imaging agent for single-photon emission computed tomography (SPECT) and positron emission tomography (PET). While a construct of 2Rs15d with the positron emitter 68Ga is currently in phase I clinical trials, the only PET images acquired in preclinical or clinical research have been within 3 h postinjection. We evaluated our in-house produced 2Rs15d nanobody, conjugated with the chelator deferoxamine (DFO), and radiolabeled with 89Zr for PET imaging up to 72 h postinjection. [89Zr]Zr-DFO-2Rs15d demonstrated high stability in both phosphate-buffered saline (PBS) and human serum. Cell binding studies showed high binding and specificity for HER2, as well as prominent internalization. Our in vivo PET imaging confirmed high-quality visualization of HER2-positive tumors up to 72 h postinjection, whereas HER2-negative tumors were not visualized. Subsequent biodistribution studies quantitatively supported the significant HER2-positive tumor uptake compared to the negative control. Our studies fill an important gap in understanding the imaging and binding properties of the 2Rs15d nanobody at extended time points. As many therapeutic radioisotopes have single or multiday half-lives, this information will directly benefit the potential of the radiotherapy development of 2Rs15d for HER2-positive breast cancer patients.


Assuntos
Antineoplásicos , Neoplasias da Mama , Anticorpos de Domínio Único , Humanos , Feminino , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Anticorpos de Domínio Único/metabolismo , Distribuição Tecidual , Trastuzumab/metabolismo , Tomografia por Emissão de Pósitrons , Receptor ErbB-2/metabolismo , Linhagem Celular Tumoral , Zircônio/química
19.
J Pathol ; 261(2): 156-168, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37555303

RESUMO

Aromatase inhibitors (Ais) are used as adjuvant endocrine therapy for oestrogen receptor-positive (ER+ve) post-menopausal breast cancer patients. Ais, by inhibiting the enzyme aromatase, block the conversion of androgen to oestrogen, reducing oestrogen levels. Resistance to Ais limits their clinical utilisation. Here, we show that overexpression of BQ323636.1 (BQ), a novel splice variant of nuclear co-repressor NCOR2, is associated with resistance to the non-steroidal aromatase inhibitor anastrozole in ER+ve post-menopausal breast cancer. Mechanistic study indicates that BQ overexpression enhances androgen receptor (AR) activity and in the presence of anastrozole, causes hyper-activation of AR signalling, which unexpectedly enhanced cell proliferation, through increased expression of CDK2, CDK4, and CCNE1. BQ overexpression reverses the effect of anastrozole in ER+ve breast cancer in an AR-dependent manner, whilst co-treatment with the AR antagonist bicalutamide recovered its therapeutic effect both in vitro and in vivo. Thus, for BQ-overexpressing breast cancer, targeting AR can combat anastrozole resistance. Clinical study of 268 primary breast cancer samples of ER+ve patients who had been treated with non-steroidal Ais showed 32.5% (38/117) of cases with combined high nuclear expression of BQ and AR, which were found to be significantly associated with Ai resistance. Non-steroidal Ai-treated patients with high nuclear expression of both BQ and AR had poorer overall, disease-specific, and disease-free survival. These findings suggest the importance of assessing BQ and AR expression status in the primary ER+ve breast tumour prior to Ai treatment. This may save patients from inappropriate treatment and enable effective therapy to be given at an early stage. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Anastrozol/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Inibidores da Aromatase/uso terapêutico , Inibidores da Aromatase/farmacologia , Estrogênios , Transdução de Sinais
20.
Clin Nucl Med ; 48(10): e468-e469, 2023 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-37566798

RESUMO

ABSTRACT: 18 F-FDG uptake in radiation pneumonitis is well documented; however, the same is less so for 18 F-floroestradiol (FES), which specifically binds to the estrogen receptors in vivo. We observed increased FES uptake in the right lung of an estrogen receptor positive breast cancer patient who had undergone right modified radical mastectomy followed by radiation therapy to chest wall. The possibility of FES uptake in radiation pneumonitis must therefore be kept in mind while interpreting FES PET.


Assuntos
Neoplasias da Mama , Pneumonite por Radiação , Humanos , Feminino , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/radioterapia , Neoplasias da Mama/metabolismo , Estradiol , Radioisótopos de Flúor , Pneumonite por Radiação/diagnóstico por imagem , Mastectomia , Tomografia por Emissão de Pósitrons
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